Genetic profile and onset features of 1005 patients with Charcot-Marie-Tooth disease in Japan

Abstract

OBJECTIVE : To identify the genetic characteristics in a large-scale of patients with Charcot-Marie-Tooth disease (CMT). METHODS: From May 2012 to August 2016, we collected 1005 cases with suspected CMT throughout Japan, whereas PMP22 duplication/deletion were excluded in advance for demyelinating CMT cases. We performed next-generation sequencing targeting CMT-related gene panels using Illumina MiSeq or Ion Proton, then analysed the gene-specific onset age of the identified cases and geographical differences in terms of their genetic spectrum. RESULTS : From 40 genes, we identified pathogenic or likely pathogenic variants in 301 cases (30.0%). The most common causative genes were GJB1 (n=66, 21.9%), MFN2 (n=66, 21.9%) and MPZ (n=51, 16.9%). In demyelinating CMT, variants were detected in 45.7% cases, and the most common reasons were GJB1 (40.3%), MPZ (27.1%), PMP22 point mutations (6.2%) and NEFL (4.7%). Axonal CMT yielded a relatively lower detection rate (22.9%), and the leading causes, occupying 72.4%, were MFN2 (37.2%), MPZ (9.0%), HSPB1 (8.3%), GJB1 (7.7%), GDAP1 (5.1%) and MME (5.1%). First decade of life was found as the most common disease onset period, and early-onset CMT cases were most likely to receive a molecular diagnosis. Geographical distribution analysis indicated distinctive genetic spectrums in different regions of Japan. CONCLUSIONS : Our results updated the genetic profile within a large-scale of Japanese CMT cases. Subsequent analyses regarding onset age and geographical distribution advanced our understanding of CMT, which would be beneficial for clinicians.

Keywords: charcot-marie-tooth disease; gene panel; molecular epidemiology; next generation sequencing.

Figure 1

Genetic spectrum of 301 cases with pathogenic or likely pathogenic variants. The following genes are indicated: GJB1 (21.9%), MFN2 (21.9%), MPZ (16.9%), HSPB1 (4.6%), PMP22 point mutation (4.3%), GDAP1 (3.0%), NEFL (3.0%), MME (2.7%), BSCL2 (2.0%), MARS (2.0%), DNM2 (1.7%), SETX (1.7%), SH3TC2 (1.7%), PRX (1.3%), GARS (1.0%), IGHMBP2 (1.0%), LRSAM1 (1.0%), AARS (0.7%), ARHGEF10 (0.7%), FGD4 (0.7%), SACS (0.7%), SBF2 (0.7%), TRPV4 (0.7%), TTR (0.7%), COA7 (0.3%), DCTN1 (0.3%), DHTKD1 (0.3%), EGR2 (0.3%), FBLN5 (0.3%), GALC (0.3%), GAN (0.3%), HARS (0.3%), HSPB3 (0.3%), HSPB8 (0.3%), INF2 (0.3%), KARS (0.3%), MTMR2 (0.3%), PRPS1 (0.3%), RAB7A (0.3%) and SOX10 (0.3%).

Figure 2

Detection rate and proportional detection of variants in cases with demyelinating and axonal CMT. *PMP22 point mutation.

Figure 3

Onset age analyses of mutation-positive cases. (A and B) Curve graph and column diagram of varied onset age and diagnostic rate of axonal or demyelinating CMT. (C) Diagram of disease onset features in cases with GJB1, MFN2, MPZ, HSPB1, PMP22 and NEFL variants. (D) Diagram of disease onset features of cases with monoallelic or biallelic variants of GDAP1 and MME genes. A, axonal type; D, demyelinating type; N, number; Y, year. *PMP22 point mutation.

Figure 4

Geographic analysis of genetic spectrum of CMT in Japan. Japan is divided into eight regions (A–H), and axonal/demyelinating type and the causative genes are indicated in different colours. Mutation-positive and total numbers of each region are indicated around the pie chart. NE, not examined.